Objective      To investigate the effects of combination of carfilzomib and Caspase inhibitor Z-VAD-FMK on the prevention and treatment of cancer cachexia and its mechanism.       Methods      Murine colon adenocarcinoma cells (C26 cells) were subcutaneously injected into male BALB/c mice to induce cancer cachexia model (with typical cachexia signs and symptoms). Then carfilzomib and Z-VAD-FMK in combination or alone were given at different time points. Body weight

tumor mass and volume

gastrocnemius muscle mass

spontaneous activity and survival time were detected. The mRNA and protein levels of Caspase 3

MuRF1 and MAFbx were detected with qRT-PCR and Western blotting

respectively.       Results      The combination of carfilzomib with Z-VAD-FMK could ameliorate weight loss in tumor-bearing mice

inhibit skeletal muscle atrophy and the growth of tumor

improve the spontaneous physiological activity

prolong the survival time and reduce the expression of MuRF1

MAFbx

and Caspase 3 in gastrocnemius muscle

showing better effects than carfilzomib or Z-VAD-FMK alone (P0.05). The effects of prevention were better than that of treatment (P0.05).       Conclusion      Ubiquitin-proteasome pathway and apoptosis pathway are inhibited by the combination of carfilzomib and Z-VAD-FMK in cancer cachexia mice

indicating that the combination can prevent and treat the development of cancer cachexia.